Estudio del appel de los linfocitos gamma-delta en la enfermedad de Crohn

Inflammatory bowel disease (IBD) is a chronic relapsing systemic disease, mainly affecting the gastrointestinal tract with extraintestinal manifestations which includes two main conditions: ulcerative colitis (UC) and Crohn´s disease (CD). It affects mainly young individuals, thus requiring the use of anti-inflammatory and immunsupressive drugs for long periods of time, with the subsequent need for specialist controls and the burden of frequent side effects. Moreover, IBD patients frequently require hospitalizations and surgical procedures, impacting directly in the medical associated costs and quality of life. The increasing incidence and prevalence of the disease and its unknown exact pathogenesis has raised the interest of an increasingly diverse group of clinicians and research groups, reinforcing the need for translational and multidisciplinary approaches. It is well recognized that an altered immune reponse to commensal intestinal bacteria takes place in genetically predisposed individuals, and it can be considered an immune deficiency condition. Attempts to bolster and regulate immunity (especially the T lymphocytes) and/or correct the immunity defects to prevent chronic inflammation represents a change of paradigme from conventional anti-inflammatory treatments to immunotherapy, that has showed positive results in other autoimmune and infectious diseases and cancer. Thus, the study of these immunological alterations, and specifically, the role of lymphocytes and their regulators in IBD, is a key element for understanding its pathogenesis, and develop new and more effective therapeutic alternatives. There are two T lymphocyte populations that can be distinguished by the expression of αβ or γδ chains. αβ T lymphocytes (αβTL) are more frequent (90-95%) in the peripheral blood, spleen and lymph nodes. On the other hand, γδ T lymphocytes (γδTL) constitute only a small proportion (1-5%) of the lymphocytes that circulate in the blood and peripheral organs, and they are present mainly in the epithelia, where they can constitute up to 50% of intraepithelial T lymphocytes (IELs). There are two major features that make γδTL different from the αβ subtype: 1)γδ TL can recognize antigens without the normal constraints of antigen processing and presentation (Major Histocompatibility Complex -MHC- restriction), providing a direct and quick response; 2)γδ TL can recognize non peptide ligands like viral proteins, bacterial superantigens, or heat shock proteins and are highly stimulated by phosphoantigens. These special features allow γδ TL to provide a comprehensive response for pathogen clearance through direct recognition, to collaborate intensely in immune modulation and in wound healing mechanisms. Interleukin 7 (IL-7) belongs to the class 1 of cytokines that signal through the common heterodimeric γc chain and has been recognized as a mediator of the homeostatic mechanisms that maintains a stable number of naive memory T cells in the peripheral immune system. Moreover IL-7 is absolutely critical for the development of γδTL, and γδTL cannot be detected in IL-7R α knockout mice. These potent immunological homeostatic properties and particularly its unique capacity of expanding naive T lymphocyte pools, make IL-7 a promising candidate for treating conditions causing T lymphocyte dysfunction or lymphopenia like chronic viral infections (HIV, CMV), regeneration of T cells after hematopoietic stem cell transplant, immunodeficiencies, autoimmune disorders and cancer immunotherapy. This could also be the case in IBD. Our hypothesis is that IBD patients present an alteration in the innate immunity, specifically in the function of γδTL and its main regulator IL-7, that contributes to the initiation and/or perpetuation of the intestinal inflammation. We aimed to determine the levels of γδTL and IL-7 in peripheral blood of 102 Crohn´s disease patients and controls and analyse its relation with several clinical and endoscopiacal variables. Our results show a decrease in the overall lymphocyte population and specially in γδTL in the peripheral blood of patients with CD. This decrease occurred in all different clinical settings and was inversely correlated with the clinical and endoscopical activity. We also found a surprising decreased level of serum IL-7 in CD –although not statistically significative- (high compensating IL-7 levels were expected due to lymphopenia). This results represents a new pathogenic mechanism in CD, with potential therapeutical implications.